CZ295190B6 - Indazole amide compound process for its preparation and pharmaceutical composition in which the compound is comprised - Google Patents

Abstract

In the present invention, there is disclosed indazole amide compound of the general formula I, in which Ri6 is selected from the group consisting of a cycloalkyl group containing 3 to 7 carbon atoms, a heterocyclic ring having 5 or 6 members and in which 1 to 4 members are identical or different hesteroatoms being selected from the group consisting of nitrogen, oxygen and sulfur, a dimethylamine alkyl group containing 1 to 3 carbon atoms in the alkyl moiety, a methoxyalkyl group having 1 to 3 carbon atoms in the alkyl moiety, an N-phenyl amide group, an aminosulfonyl methyl group, a dihydroxy alkyl group containing 2 or 3 carbon atoms or an aryl group being substituted with a hydroxy group, addition salts thereof with pharmaceutically acceptable organic and inorganic acids and pharmaceutically acceptable quaternary salts. There is also described a multistage process for preparing of the above-specified compound as well as pharmaceutical composition in which the compound is comprised. Compounds of the above-indicated type exhibit serotoninergic activity and are useful in the treatment of gastrointestinal motility, central nervous system disorders, urine incontinence and heart arrhythmia.

Description

An indazolamide compound, a process for its preparation and a pharmaceutical composition thereof

Technical field

The present invention relates to indazolamide compounds having serotoninergic activity, to a process for their preparation and to pharmaceutical compositions containing them. The invention also relates to intermediates used in the preparation of the subject indazolamide compounds.

BACKGROUND OF THE INVENTION

Among the many known classes of serotonin receptors, only 5HT ₄ receptors have recently been identified in the bladder, smooth and cardiac muscle and certain areas of the central nervous system. The compounds exhibit agonist, partially agonistic and antagonistic actions at such receptors are of potential interest in the pharmacological treatment of gastrointestinal motility disorders, central nervous system disorders, inability to maintain urine and cardiac arrhythmias. Actually, such compounds act by mimicking or antagonizing the ability of serotonin to stimulate intestinal motility by activating enteric neurons, modulating important brain processes such as training, memory and fear, inducing bladder relaxation, and increasing the frequency of atrial contractions.

We have now found a class of indazolamide compounds having affinity for 5HT ₄ receptors and acting as partial serotonin agonists or antagonists.

SUMMARY OF THE INVENTION

A first object of the present invention are to indazolamide compounds of formula I

in which

R ₆ is selected from the group consisting of C 3 -C 7 cycloalkyl, a heterocyclic ring having 5 or 6 members wherein 1 to 4 members are heteroatoms, the same or different, selected from nitrogen, oxygen and sulfur, a dimethylaminoalkyl group having C 1 -C 3 alkyl, C 1 -C 3 methoxyalkyl, N-phenylamide, aminosulfonylmethyl, C 2 -C 3 dihydroxyalkyl or hydroxy substituted aryl, their addition salts with pharmaceutically acceptable organic and inorganic acids and pharmaceutically acceptable quaternary salts thereof.

-1 CZ 295190 B6

Preferred examples of aryl groups are phenyl, naphthyl and biphenyl.

Preferred examples of heterocyclic rings are thienyl, furanyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furazanyl, pyrrolidinyl, imidazolinyl, pyrazolidyl, pyrazolinyl, piperidinyl, piperazinyl, tetrazyl, thiazyl, thiazolyl, thiazinyl, thiazolyl, triazinyl, thiazolyl . Typical examples of R ₆ are cyclopropyl, cyclohexyl, pyridyl, tetrazolyl, morpholinyl, methoxymethyl, methoxypropyl, hydroxyphenyl, dimethylaminomethyl and aminosulfonylmethyl.

A second object of the present invention is a process for the preparation of indazolamide compounds of formula I, their addition salts with pharmaceutically acceptable organic and inorganic acids, and pharmaceutically acceptable quaternary salts, which comprises:

(a) acylates 4-aminomethylpiperidine of the general formula Π

(II) in which

P is a suitable protecting group selected from benzyloxycarbonyl, benzyl, tert-butoxycarbonyl and trimethylsilylethoxycarbonyl, 1-alkylindazole-3-carboxylic acid halide of the formula HI

(III) in which:

X is a halogen atom to form a compound of formula IV

in which

P is as defined above, (IV),

-2GB 295190 B6

b) deprotecting the compound of formula IV to give a compound of formula V

(IN)

c) alkylating a compound of formula V with a compound of formula VI

(VI) in which:

R ₆ has the meanings given above and

Y is a halogen atom to give a compound of formula I,

d) optionally preparing an addition salt of an indazolamide compound of formula I with a pharmaceutically acceptable organic or inorganic acid, or a pharmaceutically acceptable quaternary salt of an indazolamide compound of formula I.

Step a) is preferably carried out by reacting a compound of formula II with a compound of formula III in which X is chlorine, in the presence of a suitable diluent and at a temperature of 0 to 140 ° C, for 0.5 to 20 hours.

Preferably, the solvent is aprotic, polar or non-polar. More preferably, the solvent is aprotic apolar. Examples of suitable aprotic apolar solvents are aromatic hydrocarbons such as benzene, toluene and xylenes. Examples of suitable aprotic polar solvents are dimethylformamide and dimethylsulfoxide.

Even more preferably, the reaction is carried out at a temperature of from 15 to 40 ° C for a period of from 1 to 14 hours.

Conversely, step b) is carried out in accordance with procedures known to those skilled in the art of protecting groups [Theodora W. Greene and Peter G.M. Wuts, "Protective groups in organic synthesis", pages 309-406, John Willey & Sons, Inc., (1991)]. In the case of benzyl and benzyloxycarbonyl, deprotection is preferably carried out by catalytic hydrogenation. An example of a suitable catalyst is palladium on activated carbon. Preferably, the deprotection is carried out by hydrogenation in the presence of a suitable solvent such as, for example, an aliphatic alcohol with a low number of carbon atoms in the chain, an aliphatic acid with a low number of carbon atoms in the chain, and mixtures thereof. An example of a preferred solvent is a mixture of ethanol and acetic acid.

Step c) is preferably carried out with a compound of formula VI wherein Y is chloro or bromo in the presence of a suitable acid acceptor such as alkali carbonates and bicarbonates, low carbon trialkylamines and a suitable solvent such as aromatic hydrocarbons , dimethylformamide and aliphatic alcohols with a low number of carbon atoms in the chain.

Typical examples of preferred organic and inorganic acids for forming addition salts of the invention (step d) are ethanedioic acid, maleic acid, tartaric acid, methanesulfonic acid, sulfuric acid, phosphoric acid, hydrobromic acid and hydrochloric acid.

Methyl iodide is a typical example of a preferred pharmaceutically acceptable quaternary salt-forming compound of the invention.

The preparation of the aforementioned salts comprises adding (step d) a pharmaceutically acceptable organic or inorganic acid, or methyl iodide, to the indazolamide compound of formula I obtained in step c).

Alternatively, the imidazolamide compound of formula I may be prepared by acylating a suitable 4-aminomethylpiperidine with a compound of formula III.

The intermediates of formula (IV) are novel compounds and are a further object of this invention.

Finally, the present invention provides a pharmaceutical composition comprising an effective dose of at least one compound of Formula I

O (I) in which

R ₆ is selected from the group consisting of C 3 -C 7 cycloalkyl, a heterocyclic ring having 5 or 6 members wherein 1 to 3 members are heteroatoms, the same or different, selected from nitrogen, oxygen and sulfur, dimethylaminoalkyl with C 1 -C 3 alkyl, C 1 -C 3 methoxyalkyl, N-phenylamide, aminosulfonylmethyl, C 2 -C 3 dihydroxyalkyl or aryl and hydroxy substituted aryl, its addition salts pharmaceutically acceptable organic and inorganic acids, or pharmaceutically acceptable quaternary salts thereof.

Typical examples of disease states that could benefit from treatment with the pharmaceutical composition of the present invention are all disease states that respond to treatment with a 5-HT ₄ receptor antagonist, such as gastrointestinal disorders associated with intestinal motility such as IBS (irritable bowel irritation) syndrome), inability to maintain urine and cardiac arrhythmias such as atrial fibrillation.

Preferably, the pharmaceutical compositions of the present invention are prepared in suitable dosage forms comprising an effective dose of at least one compound of Formula I, or a pharmaceutically acceptable addition salt or quaternary salt thereof, and at least one pharmaceutically acceptable inert ingredient.

-4GB 295190 B6

Examples of suitable dosage forms are tablets, capsules, coating tablets, granules, solutions and syrups for oral use, creams, ointments and sticky strips containing drug for topical use, suppositories for rectal administration, and sterile solutions for injection, aerosol or ophthalmic administration.

The dosage forms may also contain other conventional ingredients such as stabilizing agents, preservatives, surfactants, buffers, salts for adjusting the osmotic pressure, emulsifiers, sweeteners, coloring agents, flavoring agents and the like.

The pharmaceutical composition of the invention may, if desired for individual therapies, contain other pharmacologically active ingredients whose concomitant administration is therapeutically appropriate.

The amount of a compound of Formula I or a pharmaceutically acceptable salt thereof may vary widely depending upon known factors such as the type of disease being treated, the severity of the disease, the patient's body weight, dosage form, route of administration selected, number of daily dosage forms and effectiveness. However, the optimum amount can be readily and routinely determined by one skilled in the art.

Typically, the amount of a compound of Formula I or a salt thereof in a pharmaceutical composition of the invention will be such as to provide a dosage level of from 0.001 to 50 mg / kg per day.

Dosage forms of the pharmaceutical composition of the invention are prepared by methods known to pharmaceutical chemists and include mixing, granulating, compressing, dissolving, sterilizing and the like.

The following examples are intended to illustrate the present invention without limiting it in any way.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Preparation of 1-isopropyl-1H-3-indazolecarbonyl chloride (III: X = Cl)

a) Methylpropyl-1-isopropyl-1H-3-indazolecarboxylate

To a solution of 2-methylpropyl-1H-3-indazolecarboxylate (50 g, 0.24 mol) in 1,2-dimethoxyethane (300 mL) was added solutions of isopropyl bromide (27.5 mL, 0.29 mol) in 1,2- dimethoxyethane (100 mL) and potassium hydroxide (13.5 g, 0.24 mol), and the mixture was refluxed for 8 hours. After evaporation of the solvent, the residue was dissolved in toluene (300 ml), washed with 1N sodium hydroxide solution (100 ml), water (2 x 100 ml) and then dried and evaporated in vacuo. The residue was purified from the 2-methylpropyl-2-isopropyl-2H3-indazolecarboxylate isomer by flash chromatography (eluent hexane: ethyl acetate 95: 5) to give the title compound (23 g) as an oil.

Ή NMR (CDCl ₃ , δ): 1.07 (d, J = 7Hz, 6H), 1.66 (d, J = 7Hz, 6H), 1.95-2.48 (m, 1H), 4.26 (d, J = 7Hz), 1H), 4.96 (hept, J = 7Hz, 1H), 7.15-7.70 (m, 3H), 8.03-8.33 ( m, 1H).

-5 CZ 295190 B6

b) 1-Isopropyl-1H-3-indazolecarboxylic acid

A suspension of the compound of Example 1a) (10 g, 0.04 mol) in 0.75 N sodium hydroxide solution (100 mL) was heated at reflux for 12 hours. The solution was then cooled, acidified with 6N hydrochloric acid (40 mL), the solid precipitate was filtered off and recrystallized from 1: 1 hexane: ethyl acetate to give the title compound (5.5 g), mp 162-163 ° C [Harada H. et al., "Chem. Pharm. Bull. '43 (11) 1912-1930, (1995)].

Ή NMR (DMSO, δ): 1.54 (d, J = 7Hz, 6H), 5.13 (hept., J = 7Hz, 1H), 7.20-7.65 (m, 2H), 7.85 (d, J = 8Hz, 1H), 8.14 (d, J = 7Hz, 1H), 13.08 (broad s, 1H).

c) 1-Isopropyl-1H-3-indazolecarbonyl chloride

To a stirred solution of the compound of Example 1b) was added thionyl chloride (4 mL, 0.054 mol) and the mixture was stirred at reflux for 2 hours. After evaporation of the solvent in vacuo, the residue was recrystallized from hexane to give 3.5 g of the title compound, m.p.

mp 63-64 ° C. Elemental analysis for C H N CnHnCINzO % found: 59.29 5.20 12.76 % calculated: 59.33 4.98 12.58

Ή NMR (CDCl ₃ , δ): 1.69 (d, J = 7Hz, 6H), 5.00 (hept., J = 7Hz, 1H), 7.20-7.70 (m, 3H) 8.03-8.33 (m, 1H).

Example 2

Preparation of N-3 - {[1- (2-phenylethyl) -4-piperidinyl] methyl} -1-isopropyl-1H-3-indazolecarboxamide hydrochloride (AFR 306) (I: R ₆ = C ₆ H ₅ )

A solution of [1- (2-phenethyl) -1-piperidinyl] methylamine (3 g, 0.014 mol) prepared as described in EP-A-0 343 307 in toluene (30 ml) was added dropwise to a suspension of the compound of Example 1c) ( 3g, 0.014 mol) in toluene (30 ml). After 3 hours at room temperature, the solid was filtered, dissolved in water, basified with 6N sodium hydroxide solution and extracted with dichloromethane (2 x 200 mL). The solvent was evaporated, the residue was purified on a SiO ₂ column (eluent mixture of trichloromethane and methanol 95: 5) and converted to the corresponding hydrochloride. The product (2 g) obtained had a melting point of 211-212 ° C.

Elemental analysis for C H N cr C ₂₅ H ₃₃ C ₁ N ₄ O % found: 68.13 7.52 12.78 8.03 % calculated: 68.09 7.54 12.70 8.04

-6C 295190 B6 1 HNMR (DMSO, δ): 1.56 (d, J = 7Hz, 6H), 1.50-2.30 (m, 5H), 2.70-3.90 (m, 10H) 5.10 (hept., J = 7Hz, 1H), 7.05-7.63 (m, 7H), 7.81 (d, J = 8Hz, 1H), 8.21 (d, J = 8 Hz, 1H), 8.47 (t, J = 6 Hz, 1H), 11.05 (broad s, 1H).

IR (KBr): 1652 cm _as' ^first

Example 3

Preparation of N-3 - {[1- (2-phenylmethyl) -4-piperidinyl] methyl} -1-isopropyl-1H-3-indazolecarboxamide (IV: P = -CH ₂ C ₆ H ₅ )

To a stirred solution of 1-isopropyl-1H-3-indazolecarbonyl chloride (52 g, 0.234 mol) in toluene (300 mL) was added dropwise a solution of [1- (phenylmethyl) -4-piperidinyl] methylamine, prepared as described in WO 94/10 174 (47.7 g, 0.234 mol) in toluene (200 mL). After 5 hours, the solvent was evaporated under reduced pressure. The reaction mixture was treated with 2N sodium hydroxide solution, extracted with dichloromethane and evaporated in vacuo. The solid residue (95 g) was recrystallized from 7: 3 hexane: ethyl acetate to give the title compound as a white solid.

in the form of a white solid] (45 g), temp mp 72-74 ° C. Elemental analysis for C Η N C ₂₄ H ₃₀ ClN ₄ O % found: 73.78 7.87 14.35 % calculated: 73.81 7.74 14.35

1 H NMR (CDCl ₃ , δ): 1.59 (d, J = 7Hz, 6H), 1.10-2.25 (m, 7H), 2.80-3.15 (m, 2H), 3.27-3.60 (m, 4H), 4.86 (hept., J = 7Hz, 1H), 7.00-7.60 (m, 9H), 8.27-8.52 (m , 1H).

IR (KBr): ν _C 1641 cm ^-1 .

Example 4

Preparation of N-3- (4-piperidinylmethyl) -1-isopropyl-1H-3-indazolecarboxamide hydrochloride

A suspension of the product of Example (28 g, 0.076 mol) in ethanol (1500 mL) and glacial acetic acid (66 mL) was hydrogenated to 10% Pd-C (13.4 g) at 35 psi. for 24 hours. The mixture was filtered and the filtrate was evaporated in vacuo. The residue was dissolved in water, treated with 5N sodium hydroxide solution and stirred at room temperature for 2 hours. The solid was filtered (16.6 g) and converted to the corresponding hydrochloride (9.5 g), mp 211

and 214 ° C (dec.). Elemental analysis for C H N Ci ₇ H ₂₅ C ₁ N ₄ O.1 / 2 H ₂ O % found: 58.82 7.68 16.36 % calculated: 59.03 7.58 16.20

1 H NMR (DMSO, δ): 1.55 (d, J = 7Hz, 6H), 1.31-2.18 (m, 5H), 2.58-3.64 (m, 7H), 5 10.09 (hept., J = 7Hz, 1H), 7.12-7.60 (m, 2H), 7.80 (d, J = 8Hz, 1H), 8.20 (d, J = 8) Hz, 1H), 8.41 (t, J = 6Hz, 1H), 8.82-9.60 (m, 2H).

IR (KBr): 1658 cm _as' ^first

Example 5

Preparation of N-3 - {[1- (4-phenylbutyl) -4-piperidinyl] methyl} -1-isopropyl-1H-3-indazolecarboxamide oxalate (AFR 603) (I: R ₆ = -CH ₂ CH ₂ C ₆ H ₅ )

To a stirred suspension of the product of Example 4 as the free base (5.27 g, 15.6 mmol) in ethanol (20 mL) was added potassium carbonate (6.5 g, 50 mmol) and 4-phenylbromobutane [Braun, B- 44, 2872, (1911)] (3.6 g, 17.1 mmol). The reaction mixture was stirred at reflux for 10 hours. After evaporation of the solvent, the residue was partitioned between ethyl acetate and 1N hydrochloric acid. The aqueous layer was basified with 2N sodium hydroxide solution, extracted with ethyl acetate and evaporated in vacuo. The solid was converted to the corresponding acid salt

oxalic acid (2 g), m.p. 154-155 ° C. Elemental analysis for C H N C ₂ O ₄ 9H38ClN ₅ .l / 2 H ₂ O % found: 65.87 7.47 10.62 % calculated: 65.52 7.39 10.54

1 H NMR (DMSO, δ): 1.55 (d, J = 7Hz, 6H), 1.31-2.18 (m, 5H), 2.30-3.64 (m, 14H), δ 10.08 (hept., J = 7Hz, 1H), 7.12-7.60 (m, 7H), 7.80 (d, J = 8Hz, 1H), 8.19 (d, J = 8) Hz, 1H), 8.41 (t, J = 6Hz, 1H).

Example 6

Preparation of N-3 - {[1- (2-cyclohexylethyl) -4-piperidinyl] methyl} -1-isopropyl-1H-indazolecarboxamide hydrochloride (AFR 604) (I: R ₆ = C ₆ H _n )

Following the procedure in Example 5, N-3- (4-piperidinylmethyl) -1-isopropyl-1H-3-indazolecarboxamide (4.42 g) and (2-bromoethyl) cyclohexane provided [JACS, 48, 1089-1093 (1926)] title compound (2.5 g), m.p. 244-246 ° C (dec.).

Elemental analysis for C H N Cl C ₂₅ H ₃₉ N ₄ Ol / 2 H ₂ O % found: 65.51 9.05 12.54 7.89 % calculated: 65.83 8.84 12.28 7.77

-8EN 295190 B6

1 H NMR (DMSO, δ): 1.55 (d, J = 7Hz, 6H), 0.68-2.18 (m, 17H), 2.63-3.70 (m, 10H), 09 (hept., J = 7Hz, 1H), 7.12-7.60 (m, 2H), 7.80 (d, J = 8Hz, 1H), 8.20 (d, J = 8Hz) 1 H, 8.41 (t, J = 6 Hz, 1 H), 10.70 (broad s, 1H).

IR (KBr): 1656 cm _as ^{the first}

Example 7

Preparation of N-3 - {{1- [3- (dimethylamino) propyl-4-piperidinyl} methyl} -1-isopropyl-3-indazolecarboxamide (AFR 606) dimaleate (I: R ₆ = -CH ₂ NC ₂ H ₆ )

Following the procedure of Example 5, N-3- (4-piperidinylmethyl) -1-isopropyl-1H-3-indazolecarboxamide (3 g) and N- (3-chloropropyl) -N, N-dimethylamine hydrochloride (580 mg) and the compound title compound (950 mg), m.p. 155-156 ° C.

Elemental analysis for C

C ₃₀ H ₄ N ₅ O ₉ .1 / 2 H ₂ O% found: 57.83% calculated: 57.50

7.01 11.11

7.08 11.18 1 H NMR (DMSO, δ): 1.55 (d, J = 7 Hz, 6H), 1.68-2.28 (m, 7H), 2.81 (s, 6H) 2.75-3.75 (m, 11H), 5.09 (hept., J = 7Hz, 1H), 6.09 (s, 4H), 7.12-7.60 (m, 2H) 7.81 (d, J = 8Hz, 1H, 8.20 (d, J = 8Hz), 1H), 8.45 (t, J = 6Hz, 1H).

Example 8

Preparation of N-3 - {{1- [2- (4-morpholinyl) ethyl] -4-piperidinyl} methyl} -1-isopropyl-1H-3-indazolecarboxamide dihydrochloride (ARF 607) (I: R ₆ = -C 4 H 4 NO)

Following the procedure of Example 5, N-3- (4-piperidinylmethyl) -1-isopropyl-1H-3-indazolecarboxamide (3 g) and 4- (2-chloroethyl) morpholine (3.42 g) gave the title compound.

(3.2 g), m.p. 266 DEG-267 DEG C. (dec.). Elemental analysis for C H N Cl C ₂₃ H ₃₇ Cl ₂ N ₅ O ₂ .l / 2 H ₂ O % found: 55.74 7.61 13.96 14.12 % calculated: 55.75 7.73 14.13 14.31

1 H NMR (DMSO, δ): 1.55 (d, J = 7 Hz, 6H), 1.30-2.25 (m, 5H), 2.75-4.30 (m, 19H), δ 10.09 (hept., J = 7Hz, 1H), 7.12-7.60 (m, 2H), 7.81 (d, J = 8Hz, 1H), 8.20 (d, J = 8) Hz, 1H), 8.45 (t, J = 6 Hz, 1H), 10.80 (broad s, 1H), 10.60 (broad s, 1H).

IR (KBr): 1652 cm _as' ^first

-9EN 295190 B6

Example 9

Preparation N-3 - {{1- [2 - [(methylsulfonyl) amino] ethyl] -4-piperidinyl} methyl} -isopropyl-1H-3-indazolecarboxamide hydrochloride (AFR 703) (I: R ₆ : CH ₃ SO ₂ NH-)

Following the procedure of Example 5, N3- (4-piperidinylmethyl) -1-isopropyl-1H-3-indazolecarboxamide (5 g) and N- (bromoethyl) methyl sulfonamide [WO 93/18036] (3 g) gave the title compound. 186 DEG-187 DEG C. (decomposition).

Elemental analysis for C H N WITH Cl C ₂₀ H ₃₂ ClN ₅ O ₃ S % found: 52.15 7.22 15.30 6.98 7.77 % calculated: 52.45 7.04 15.29 7.00 7.74

Ή NMR (DMSO, δ): 1.55 (d, J = 7Hz, 6H), 1.40-2.30 (m, 5H), 3.00 (s, 3H), 2.75-3, 80 (m, 10H), 5.09 (hept., J = 7Hz, 1H), 7.12-7.70 (m, 3H), 7.80 (d, J = 8Hz, 1H), 8 20 (d, J = 8Hz), 7.12-7.70 (m, 3H), 7.80 (d, J = 8Hz, 1H), 8.20 (d, J = 8Hz, 1H) 8.45 (t, J = 6Hz, 1H), 10.73 (broad s, 1H).

IR (KBr): V _CO 1651 cm ^-1 .

Example 10

Preparation of N-3 - {{1- [2- (2-pyridinyl) ethyl] -4-piperidinyl} methyl} -1-isopropyl-3-indazolecarboxamide hydrochloride (AFR 605) (I: R ₆ = C ₅ H ₄ N )

To a stirred suspension of the product of Example 4 as the free base (10 g, 33.3 mmol) was added 2-vinylpyridine (3.6 g, 34 mmol), glacial acetic acid (2 mL) and water (2.5 mL). . After 16 hours at 95 ° C, the reaction mixture was basified with 2N sodium hydroxide solution, extracted with ethyl acetate and evaporated in vacuo. The residue was purified by flash chromatography on silica gel using a 97: 3 mixture of trichloromethane and methanol as eluent to give a solid which was converted to the corresponding hydrochloride (5g), m.p. 122-123 ° C (dec.).

Elemental Analysis for C pro.?

N Cl

C ₂₄ H ₃₂ C1N ₅ O ₃ .H ₂ O% found:

% calculated:

62.80 7.42

62.66 7.45

15.18 7.78

15.22 7.71

Ή NMR (DMSO, δ): 1.55 (d, J = 7Hz, 6H), 1.68-2.30 (m, 5H), 2.80-3.78 (m, 12H), 10 (hept., J = 7Hz, 1H), 7.12-7.60 (m, 4H), 7.68-8.00 (m, 2H), 8.21 (d, J = 7Hz, 1H), 8.33-8.70 (m, 2H), 11.05 (br s, 1H)

IR (KBr): 1644 cm _as' ^first

-10GB 295190 B6

Test 1

5-HT ₄ receptor antagonist activity

The antagonistic action of the compound of formula I was evaluated by testing the effect of the compound during the evaluation on the serotonin-induced release of the esophageal envelope pre-extracted by carbachol according to the method described by J. D. Gale et al. in "Br. J. Pharmacol., 111, 332-338 (1994).

All test compounds of the invention exhibited pA ₂ > 8. Specific values for ARF 603, AFR 604, AFR 605, and AFR 306 are shown in Table 1 below.

Table 1

Compound pA ₂ standard error AFR 603 9.12 1.42 ARF 604 8.19 0.99 AFR 605 10.8 1.90 AFR 306 9.36 0.38

PATENTOVÉ

Claims

Claims (16)

An indazolamide compound of formula I O in which R ₆ is selected from the group consisting of C 3 -C 7 cycloalkyl, a heterocyclic ring having 5 or 6 members wherein 1 to 4 members are heteroatoms, the same or different, selected from nitrogen, oxygen and sulfur, a dimethylaminoalkyl group having C 1 -C 3 alkyl, C 1 -C 3 methoxyalkyl, N-phenylamide, aminosulfonylmethyl, C 2 -C 3 dihydroxyalkyl or hydroxy substituted aryl, its addition salts with pharmaceutically acceptable organic and inorganic acids and pharmaceutically acceptable quaternary salts thereof. A compound according to claim 1, wherein the heterocyclic rings are thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furaza Nyl, pyrrolidinyl, imidazolinyl, pyrazolidyl, pyrazolinyl, piperidinyl, piperazinyl, morpholinyl, triazinyl, thiazolyl, tetrazolyl and thiadiazolyl. A compound according to claim 1, wherein R ₆ is selected from the group consisting of cyclopropyl, cyclohexyl, pyridyl, tetrazolyl, morpholinyl, methoxymethyl, methoxypropyl, hydroxyphenyl, dimethylaminomethyl and aminosulfonylmethyl. A compound according to claim 1, wherein R 6 is cyclohexyl. A compound according to claim 1, wherein R 6 is pyridyl. A compound according to claim 1, wherein R 6 is dimethylaminomethyl. A compound according to claim 1, wherein R 6 is morpholinyl. A compound according to claim 1, wherein R 6 is aminosulfonylmethyl. A process for the preparation of a compound according to claim 1, the addition salts thereof with pharmaceutically acceptable organic and inorganic acids and their pharmaceutically acceptable quaternary salts, characterized in that (a) acylates a 4-aminomethylpiperidine of formula (II) wherein: P is a suitable 1-alkylindazole-3-carboxylic acid halide of formula III O (III), in which X is a halogen atom to form a compound of formula IV (IV), -12GB 295190 B6 in which P is a suitable protecting group selected from benzyloxycarbonyl, benzyl, tert-butoxycarbonyl and trimethylsilylethoxycarbonyl, b) deprotecting the compound of formula IV to give a compound of formula V (V) c) alkylating a compound of formula V with a compound of formula VI (VI) wherein: R ₆ has the meanings given above and Y is a halogen atom to give a compound of formula I, d) optionally preparing an addition salt of an indazolamide compound of formula I with a pharmaceutically acceptable organic or inorganic acid, or a pharmaceutically acceptable quaternary salt of an indazolamide compound of formula I. 10. The method of claim 9 wherein P is selected from the group consisting of benzyloxycarbonyl, benzyl, tert-butoxycarbonyl, and trimethylsilylethoxycarbonyl. Process according to claim 9 or 10, characterized in that step a) is preferably carried out by reacting a compound of formula II with a compound of formula III in which X is chlorine in the presence of a suitable solvent and at a temperature of 0 ° C to 140 ° C, for 0.5 to 20 hours. 12. The process of claim 10 wherein when P is benzyl or benzyloxycarbonyl, step b) is carried out by catalytic hydrogenation. Process according to any one of the preceding claims 9 to 11, characterized in that when in the compound of the general formula VI Y is chlorine or bromine, step c) is carried out in the presence of an acid acceptor and in the presence of a solvent. 14. The process of claim 9 wherein the methyl iodide is a pharmaceutically acceptable quaternary salt of the compound of Formula I, step d). -13EN 295190 B6 (IV) An indazolamide compound of formula IV wherein: P is selected from the group consisting of benzyloxycarbonyl, tert-butoxycarbonyl, and trimethylsilylethoxycarbonyl. 16. A pharmaceutical composition comprising an effective dose of at least one compound of formula (I) O in which R e is selected from the group consisting of C 3 -C 7 cycloalkyl, a heterocyclic ring having 5 or 6 members wherein 1 to 3 members are heteroatoms, the same or different, selected from nitrogen, oxygen and sulfur, a 1-dimethylaminoalkyl group up to 3 carbon atoms in the alkyl moiety, methoxyalkyl of 1 to 3 carbon atoms in the alkyl moiety, N-phenylamide, aminosulfonylmethyl, dihydroxyalkyl of 2 or 3 carbon atoms or aryl and aryl-substituted aryl groups, pharmaceutically acceptable salts thereof acceptable organic and inorganic acids, or pharmaceutically acceptable quaternary salts thereof.